Efficient photocaging of a tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase

Sõrmus, Tanel; Lavõgina, Darja; Enkvist, Erki; Uri, Asko; Viht, Kaido

doi:10.1039/c9cc04978a

Cited by 12 publications

(15 citation statements)

References 45 publications

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“… 175 − 177 The tail absorption of 8a in the visible range (398–440 nm) was sufficient to promote the photoreaction. 175 , 178 Introducing electron-donating groups (EDG) at the 7-position of NDBF ( 8b and 8c ) led to a bathochromic shift in λ max abs but also reduced its photouncaging quantum efficiency ( Table 4 ). 151 , 174 The low quantum yield of 8c was attributed to a charge-transfer transition following photoexcitation that competes with LG release.…”

Section: Photorelease From Organic Photoactivatable Compoundsmentioning

confidence: 99%

“… However, due to the reduction in quantum efficiency, the uncaging cross section (Φ r ε(λ irr )) of the latter group tends to be comparable to that of the parent oNB 5a . ,, Nitrodibenzofuran 8a (NDBF; Figure ), introduced by Ellis-Davies and co-workers, is an exceptional red-shifted oNB derivative that releases LGs efficiently . The photolysis of ether, thioether, and phosphoester , LGs caged with this group reportedly proceeded with Φ r values of 0.5–0.7, although lower quantum yields were obtained in some cases (0.04–0.2). − The tail absorption of 8a in the visible range (398–440 nm) was sufficient to promote the photoreaction. , Introducing electron-donating groups (EDG) at the 7-position of NDBF ( 8b and 8c ) led to a bathochromic shift in λ max abs but also reduced its photouncaging quantum efficiency (Table ). , The low quantum yield of 8c was attributed to a charge-transfer transition following photoexcitation that competes with LG release. , Ball and co-workers recently reported that derivatives of 8a and 8c undergo efficient photocleavage of C(sp 2 )–N bonds .…”

Section: Photorelease From Organic Photoactivatable Compoundsmentioning

confidence: 99%

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Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

et al. 2020

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Photoactivatable (alternatively, photoremovable, photoreleasable, or photocleavable) protecting groups (PPGs), also known as caged or photocaged compounds, are used to enable non-invasive spatiotemporal photochemical control over the release of species of interest. Recent years have seen the development of PPGs activatable by biologically and chemically benign visible and near-infrared (NIR) light. These long-wavelength-absorbing moieties expand the applicability of this powerful method and its accessibility to non-specialist users. This review comprehensively covers organic and transition metal-containing photoactivatable compounds (complexes) that absorb in the visible- and NIR-range to release various leaving groups and gasotransmitters (carbon monoxide, nitric oxide, and hydrogen sulfide). The text also covers visible- and NIR-light-induced photosensitized release using molecular sensitizers, quantum dots, and upconversion and second-harmonic nanoparticles, as well as release via photodynamic (photooxygenation by singlet oxygen) and photothermal effects. Release from photoactivatable polymers, micelles, vesicles, and photoswitches, along with the related emerging field of photopharmacology, is discussed at the end of the review.

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Section: Photorelease From Organic Photoactivatable Compoundsmentioning

confidence: 99%

Section: Photorelease From Organic Photoactivatable Compoundsmentioning

confidence: 99%

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

et al. 2020

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“…The inhibitory properties of the potent bi‐substrate inhibitor 2 of cAMP‐dependent protein kinase (PKAcα) was masked by the inclusion of a nitrodibenzofuran (NDBF)‐derived caging group onto the nitrogen atom of the pyrimidine heterocycle, preventing key hydrogen bond interactions from occurring in the ATP binding site (Figure 2). [8] The binding affinity of the caged inhibitor 1 for PKAcα was 1900 nM K D . Irradiation of the caged inhibitor using a Hg vapour lamp resulted in a significant decrease in affinity for PKAcα by 5‐orders of magnitude ( K D <0.1 nM).…”

Section: Light‐responsive Kinase Inhibitorsmentioning

confidence: 98%

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

Laczi

Johnstone

Fleming

2022

Chemistry An Asian Journal

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The development of new and effective therapeutics is reliant on the ability to study the underlying mechanisms of potential drug targets in live cells and multicellular systems. A persistent challenge in many drug development programmes is poor selectivity, which can obscure the mechanisms involved and lead to poorly understood modes of action. In efforts to improve our understanding of these complex processes, small molecule inhibitors have been developed in which their OFF/ON therapeutic activity can be toggled using light. Photopharmacology is devoted to using light to modulate drugs. Herein, we highlight the recent progress made towards the development of light‐responsive small molecule inhibitors of selected enzymatic targets. Given the size of this field, literature from 2015 onwards has been reviewed.

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“…An example of a photocaged bisubstrate inhibitor ( Figure 1 a) of protein kinases (PKs) was recently published by our group [ 22 ]. PKs are transferases that catalyze protein phosphorylation, a key reaction of regulation of cell’s life.…”

Section: Introductionmentioning

confidence: 99%

“…The conjugation of the fragments yields inhibitors with a remarkable potency, where the lowest K D values of ARCs are in the low picomolar range. The attachment of a single nitrodibenzofuran (NDBF) photocage to a hot-spot position on the ATP-binding site-targeting fragment efficiently blocked the binding of ARC to the catalytic subunit type α of cAMP-dependent PK (PKAcα), as shown by the five orders of magnitude affinity difference between the photocaged ( K D = 1.9 µM) and active ( K D = 5 pM) forms of the inhibitor [ 22 ]. Furthermore, several examples of bivalent (and multivalent) ligands have been published whose multivalent binding is controlled by a photoswitch ( Figure 1 d) [ 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Deactivatable Bisubstrate Inhibitors of Protein Kinases

et al. 2022

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Bivalent ligands, including bisubstrate inhibitors, are conjugates of pharmacophores, which simultaneously target two binding sites of the biomolecule. Such structures offer attainable means for the development of compounds whose ability to bind to the biological target could be modulated by an external trigger. In the present work, two deactivatable bisubstrate inhibitors of basophilic protein kinases (PKs) were constructed by conjugating the pharmacophores via linkers that could be cleaved in response to external stimuli. The inhibitor ARC-2121 incorporated a photocleavable nitrodibenzofuran-comprising β-amino acid residue in the structure of the linker. The pharmacophores of the other deactivatable inhibitor ARC-2194 were conjugated via reduction-cleavable disulfide bond. The disassembly of the inhibitors was monitored by HPLC-MS. The affinity and inhibitory potency of the inhibitors toward cAMP-dependent PK (PKAcα) were established by an equilibrium competitive displacement assay and enzyme activity assay, respectively. The deactivatable inhibitors possessed remarkably high 1–2-picomolar affinity toward PKAcα. Irradiation of ARC-2121 with 365 nm UV radiation led to reaction products possessing a 30-fold reduced affinity. The chemical reduction of ARC-2194 resulted in the decrease of affinity of over four orders of magnitude. The deactivatable inhibitors of PKs are valuable tools for the temporal inhibition or capture of these pharmacologically important enzymes.

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Efficient photocaging of a tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase

Abstract: PKA bisubstrate inhibitor photocaging resulted in an over 5 orders of magnitude affinity difference between the photocaged and the active inhibitor.

Cited by 12 publications

References 45 publications

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

Deactivatable Bisubstrate Inhibitors of Protein Kinases

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